The present invention claims priority on Taiwanese application number 90131897, filed on Dec. 21, 2001, which is herein incorporated by reference.
The present invention relates to herbal pharmaceutical compositions which contain the root of scutellaria (Radix Scutellariae), the rhizome of coptis (Rhizoma Coptidis), the root and rhizome of rhubarb (Radix et Rhizoma Rhei), and the root of ginseng (Radix Ginseng) or American ginseng (Radix Panacis Quinquefolii) for prophylaxis or treatment of cardiovascular diseases. Optionally, the root of ginseng or American ginseng can be replaced with the rhizome of ginger (Rhizoma Zingiberis). The herbs can be prepared as dry powders or extracts. The present invention also relates to the methods of preparing and using the herbal pharmaceutical compositions.
Based on data from the World Health Organization (WHO), cardiovascular diseases contribute to a third of global deaths in 1999 and are estimated to be the leading cause of death in developing countries by 2010. Cardiovascular diseases are the name for a group of disorders in the heart and blood vessels, including, but not limited to, hypertension (high blood pressure), coronary heart disease (heart attack), cerebrovascular disease (stroke), peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease, and cardiomyopathies.
Hypertension is by far the most prevalent cardiovascular disease. It is estimated that more than a third of Americans aged 45 or older have high blood pressure and, among them, more than 50% are aged 60 or older. Untreated hypertension can lead to serious and life-threatening complications, e.g., stroke, coronary heart disease, arteriosclerosis, atherosclerosis, heart failure, kidney failure and blindness.
As indicated in the United States Sixth Report of the Joint National Committee (JNC VI) on High Blood Pressure, current treatment for hypertension includes diuretics, xcex1-blockers, xcex2-blockers, calcium channel blockers, ACE inhibitors, and angiotensin antagonists. These agents can be used as monotherapy or in combination. However, most of these agents ameliorate the symptoms but not curing the diseases. These agents are also frequently accompanied with side effects.
One of the major mechanisms for causing human hypertension is the dysfunction of endothelium. Endothelium is the layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels. Its main role is to modulate both vascular tone and structure by producing vasodilator and vasoconstrictor mediators.
When activated by specific agonists such as acetylcholine, endothelial cells produce nitric oxide (xe2x80x9cNOxe2x80x9d), a labile substance derived by L-arginine degradation through the activity of the endothelial NO synthase (xe2x80x9ceNOSxe2x80x9d). NO is a powerful relaxing agent which also inhibits platelet aggregation and smooth muscle cell proliferation.
Under pathological conditions, such as hypertension or aging, agonist-induced stimulation of endothelium leads to activation of a cyclooxygenase pathway and consequent production of cyclooxygenase-dependent factors, including thromboxane A2 or prostaglandin H2, or free radicals (such as superoxide anions). Dysfunctional endothelium can also cause vascular damage, in particular, atherosclerosis.
There are two isoforms of cyclooxygenase, cyclooxygenase 1 and 2 (COX-1 and COX-2), also referred to as prostaglandin endoperoxide synthase 1 and 2, which are key enzymes in the conversion of arachidonic acid to prostaglandins, thromboxanes and other eicosanoids. It is believed that COX-1 and COX-2 have different physiologic functions due to striking differences in their tissue expression and regulation. COX-1 is a constitutive enzyme that is present at all times in the body and is responsible for the production of cytoprotective prostaglandins important for homeostatic functions, such as maintaining the integrity of the gastric mucosa, mediating normal platelet function, and regulating renal blood flow. In contrast, COX-2 is a rapidly inducible form of cyclooxygenase that leads to the production of proinflammatory prostaglandins. While COX-2 expression is highly restricted under basal conditions, it is dramatically up-regulated during inflammation. The involvement of COX-2 and the elevated production of prostaglandins are associated with a variety of diseases and disorders, such as brain ischemia and cancers, as well as diseases and disorders in which elevated levels of NO is present.
NO modulates the activity of COX-2 and participates in inflammatory and autoimmune-mediated tissue destruction. The effect of NO on COX-2 is dose-dependent. Low levels of NO activate COX-2. In contrast, large amounts of NO produced by inducible nitric oxide synthase (xe2x80x9ciNOSxe2x80x9d) can inhibit the induction of COX-2 and suppress the formation of COX-2 metabolites.
iNOS is expressed in the myocardium after myocardial infarction (MI) and in heart failure. Myocardium is the middle and thickest layer of the heart wall composes of cardiac muscle. Upregulation or overexpression of iNOS is associated with mild inflammatory cell infiltrate, cardiac fibrosis, hypertrophy, and dilatation. Cardiac hypertrophy is a significant risk factor for the development of congestive heart failure (CHF). Overexpression of iNOS results in overproduction of NO, causing myocardial dysfunction and CHF.
CHF is a form of heart disease in which weakened heart function exists with concomitant edema. CHF has many different causes, including narrowing of the arteries supplying blood to the heart muscle (coronary heart disease), prior heart attack (myocardial infarction) resulting in scar tissue large enough or located so to interfere with normal electrocardiac function, high blood pressure, etc. CHF is one of the most serious cardiovascular diseases affecting adults. Over 4 million people have CHF and the incidence is on the rise. The incidence of this disease or condition is increasing with the aging of the population and is currently the mast common cause for hospital admission in the elderly. The total U.S. healthcare expenditure on CHF is over five billion dollars per year.
Atrial fibrillation (AF) is atrial arrhythmia characterized by rapid randomized contractions of the atrial myocardium, causing a totally irregular, often rapid ventricular rate. AF may persist due to structural changes in the atria that are promoted by inflammation. C-reactive protein (CRP) is a marker of systemic inflammation which predicts cardiovascular events and stroke, a common sequela of AF. CRP also induces adhesion molecule expression by endothelial cells.
While a panacea has been hunted for in western medicine for years, researchers turn to traditional Chinese herbal medicine for medications of various diseases. Chinese herbal medicine has existed and been use for treating various diseases for thousands of years.
For example, San-Huang-Hsie-Hsin-Tang is an ancient herbal decoction which was first described in Chin-Kuei-Yao-Lueh (translated into English as xe2x80x9cthe Prescriptions From the Golden Chamberxe2x80x9d) for xe2x80x9cpurging fire and clearing the three torsosxe2x80x9d and wherefore it is indicated for insufficient cardiac xe2x80x9cChi,xe2x80x9d hematemesis, and epistaxis. The decoction is made of equal amounts of the root of scutellaria (Radix Scutellariae), the rhizome of coptis (Rhizoma Coptidis), and the root and rhizome of rhubarb (Radix et Rhizoma Rhei). The decoction has a bitter taste and with a cold nature. The decoction is intended for patients with congestion, flush up, fidgets, shoulder stiffness, gastric obstructive depression, constipation, and forceful pulse. However, the decoction is contraindicated for not suitable for patients with symptoms of prolonged bleeding, marked anemia, and minute-weak pulses.
U.S. Pat. No. 5,443,839 discloses a composition having anti-inflammatory, anti-allergic or anti-aging activity comprising, inter alia, an extract of Scutellaria. There is no indication that the composition is effective in treating cardiovascular disease and hypertension.
U.S. Pat. No. 6,274,177 discloses a method of preparing an extract from Zingiber officinale, which is potent in anti-inflammation and anti-platelet aggregation. There is no indication that the herbal composition is effective in treating cardiovascular disease and hypertension.
U.S. Pat. No. 6,340,480 discloses a composition and method for treating circulatory conditions including hypertension by promoting systemic vascular relaxation and dilation. The composition is a natural combination of L-arginine, ginseng, and Zizyphi fructus in an orally or topically administered form. The combination works synergistically to synthesize NO and thereby promote systemic vascular relaxation and dilation. The combined constituents may work to maintain a critical threshold level of NO in areas that cannot themselves produce it, thereby promoting systemic vascular relaxation and dilation in order to reduce hypertension. However, it is not clear whether the herbal composition is effective in treating cardiovascular disease.
In the invention to be presented in the following section, an herbal pharmaceutical composition is described. This herbal pharmaceutical composition is effective in both prophylaxis and treatment of cardiovascular diseases. The composition is also non-toxic and thus can be used by patients in all ages and physical conditions, including the week, the early and the debilitated.
In addition, the herbal pharmaceutical composition of the present invention provides multiple mechanisms of pharmacologically effects, including lowering and stabilization of blood pressure; inhibition of expression of iNOS; inhibition of COX-2 activity; reduction of blood CRP; and reduction of blood cholesterol.
The present invention provides herbal pharmaceutical compositions which contain Radix scutellariae (root of scutellaria); Rhizoma Coptidis (rhizome of coptis); Radix et Rhizoma Rhei (root and rhizome of rhubarb); and Radix Ginseng (root of ginseng) or Radix Panacis Quinquefolii (American ginseng). The preferred weight ratio of the root of scutellaria, the rhizome of coptis, the root and rhizome of rhubarb, and the root of ginseng or American ginseng is about 1-2:1-2:1-2:1-2; and most favorably 1:1:1:1. Optionally, the root of ginseng or American ginseng can be replaced with Rhizoma Zingiberis (rhizome of ginger). The preferred weight ratio of the root of scutellaria, the rhizome of coptis, the root and rhizome of rhubarb, and the rhizome of ginger is about 1-2:1-2:1-2:1-2; and most favorably 1:1:1:1.
The herbs of the present invention can be prepared in the form of dry powders or extracts. The herbal pharmaceutical composition containing dry powders of the root of scutellaria, the rhizome of coptis, the root and rhizome of rhubarb, and the root of ginseng or American ginseng (as shown in Example 1, infra) is pharmaceutically active and possesses the properties of lowering and maintaining blood pressure as well as treating other cardiovascular diseases. However, the preferred pharmaceutical compositions of the present invention are the ones containing a mixture of both herbal extracts and dry powders. Preferably, the root of scutellaria, the rhizome of coptis, and the root and rhizome of rhubarb are prepared as extracts, where the active ingredients of the herbs are extracted by a solvent, which can be water, alcohol, or a mixture thereof. The preferred solvent for the root of scutellaria and the rhizome of coptis is water. The preferred solvent for the root and rhizome of rhubarb is alcohol, most favorably 95% alcohol (in water).
The preferred form of ginseng/American ginseng or ginger used in the herbal pharmaceutical compositions is dry powders, which are prepared by cutting and grinding the herbs, followed by drying.
In addition to the herbs, the herbal pharmaceutical compositions of the present invention can contain a pharmaceutically acceptable excipient and/or carrier and be formulated in various dosage form such as granule, capsule, tablet, powder, and bolus, for orally administration. The preferred formulation is tablet.
The present invention provides a methods for preparing the herbal pharmaceutical compositions which contain a mixture of herbal extracts and dry powders as follows: (1) individually extracting the root of scutellaria, the rhizoma of coptis, and the root and rhizome of rhubarb with an appropriate solvent to form respective extracts of the herbs; (2) individually filtering the respective extracts of the herbs; (3) mixing the respectively filtered extracts of the herbs to form an herbal mixture; (4) condensing the herbal mixture to form an herbal paste; (5) grinding the root of ginseng or American ginseng to make dry powders of ginseng or American ginseng; (6) adding the dry powders of ginseng or American ginseng to the herbal paste; and (7) drying the paste to form the herbal pharmaceutical compositions.
Optionally, the root of ginseng or American ginseng can be replaced with Rhizoma Zingiberis (rhizome of ginger).
The root of scutellaria and the rhizome of coptis are preferably extracted by water. The root and rhizome of rhubarb can either be extracted by alcohol or by a mixture of alcohol and water, preferably 95% alcohol in water.
The herbal pharmaceutical composition of the present invention has therapeutic effect on cardiovascular diseases and can be used for prevention and/or treatment of cardiovascular diseases, including, but not limited to, hypertension, coronary heart disease, cerebrovascular disease, peripheral vascular disease, heart failure, rheumatic heart disease, congenital heart disease, and cardiomyopathies.
Specifically, the herbal pharmaceutical composition of the present invention can stabilize and lower blood pressure, prevent damage to endothelial cell (e.g., by inhibiting iNOS activity, inhibiting COX-2 activity, reducing blood CRP concentration, inhibiting smooth muscular cell proliferation, and reduce blood cholesterol level). The herbal pharmaceutical composition can be safely used by patients at any ages and physical conditions, including the weak, the elderly, and the debilitated.